Genetic factors contribute to the risk of sudden death from cardiac arrhythmias. As a result of this grant we have defined three arrhythmias- susceptibility genes: HERG; SCN5A; minK. The goal of the present application is to define novel genes responsible for cardiac arrhythmia. This will facilitate prediction, prevention and treatment of familial arrhythmias and may provide insight into more common disorders. The Specific Aims are: 1. Ascertain and Phenotypically characterize familial and sporadic cases of ventricular arrhythmias. We will ascertain and collect DNA samples from individuals with familial ventricular tachyarrhythmias using existing referral sources. Although we have sufficient material for initial work, continued ascertainment will improve the likelihood of success during latter work. 2. Define the chromosomal location of novel arrhythmia loci. The chromosomal location of novel arrhythmia genes will be determined using genetic linkage analysis. 3. Identify novel ventricular arrhythmia genes using complementary approach: Once a novel arrhythmia locus has been identified, a gene previously mapped to that region may become a candidate based on its position. The candidacy of a gene will be tested using linkage and mutational analyses. If a novel arrhythmia gene is not defined using candidates already mapped to that locus. New candidates will be identified using positional cloning. The candidacy of genes identified by a physiologic rationale (e.g. cardiac ion channel alpha and beta sub-units) and ion channels modulators) will be tested in unlinked populations using mutational analyses. 4. Define the genomic structure of novel arrhythmia genes and complete mutational analyses preparation for future genetic testing. We will define the genomic structure of novel arrhythmia genes and use this information for mutational analyses in susceptible populations. A catalog of arrhythmia-associated mutations will be generated for use in prediction and prevention of life-threatening ventricular arrhythmias.